Asthma is a chronic inflammatory disease of the lung that results in airway remodeling and acute pulmonary allergic responses that can be debilitating or fatal. Many individuals with severe asthma do not respond or are poorly responsive to current therapies and alternative methods to treat or manage this disease are essential. One approach that may allow specific control over immunity in asthma is to influence differentiation pathways of mature CD4 T cells into effector (Teff) or inducible regulatory (Treg) subsets. Asthma has been associated with an imbalance of these subsets marked by increased frequency of Teff and decreased Treg cells, yet mechanisms that control this balance are poorly understood. We propose that modulation of T cell metabolism may provide a new approach to manipulate CD4 T cell differentiation and treat asthma. We have shown that T cell stimulation promotes a switch from an oxidative to a predominantly glycolytic metabolism in which glucose-derived pyruvate is converted to lactate or used to support biosynthesis rather than mitochondrial oxidation. Cell metabolism must, however, be tuned to specific cellular demands and consistent with the distinct roles and activities of Teff and Treg CD4 T cells, we found that differentiated CD4 T cell subsets had distinctly different metabolic patterns and requirements. Specifically, Teff cells were highly glycolytic and required glucose for metabolism and survival while Treg cells remained oxidative and required lipids for mitochondrial oxidation. Further, we found that the nuclear hormone receptor Estrogen Related Receptor-alpha (ERRa) was activated following T cell stimulation and essential to promote increased glucose metabolism of Teff. Importantly, inhibition of ERRa selectively suppressed Teff generation whereas treatment of mice with activators of AMP-protein kinase (AMPK) to directly promote oxidative metabolism increased Treg generation in vivo. Together these findings have led to the hypothesis that T cell metabolism is a critical factor in T cell differentiation into effector or regulatory populations with glycolytic metabolism favoring inflammatory effector and oxidative metabolism favoring regulatory T cells and that manipulation of T cell metabolism through ERRa and AMPK may allow for selective Treg generation to suppress allergic asthma. To test this hypothesis we propose to: (1) Determine how metabolism influences CD4 T cell differentiation into Treg or Teff populations; (2) Examine the role of ERRa in regulation of T cell metabolism and differentiation; and (3) Establish how modulation of T cell metabolism in vivo impacts a model of allergic asthma. Together these aims will define the regulation and role of Teff and Treg metabolic programs and point towards metabolic regulatory mechanisms that can be targeted in novel therapies to treat or control asthma. PUBLIC HEALTH RELEVANCE: Asthma is a chronic inflammatory disease of the lung that results in airway remodeling and acute pulmonary allergic responses that can be debilitating or fatal and many individuals with severe asthma respond poorly to current therapies. Modulation of CD4 T cell differentiation into inflammatory effector or suppressive regulatory subtypes may prevent or treat asthma and we have found that control of cell metabolism can have a strong influence on these CD4 T cell fates. This study will examine the role and regulation of metabolism in T cell differentiation and asthma to explore new directions in the treatment of allergic asthma.